The carcinogenic process is complex and often involves changes in the expression of two contrasting genetic elements, i.e., positive acting oncogenes and negative acting anti-oncogenes (tumor suppressor genes) (for reviews see references 1-3). Compounds displaying selective toxicity toward transformed cells overexpressing different classes of oncogenes could prove useful as potential antitumor agents and as reagents for identifying cellular targets susceptible to modification by transforming oncogenes.
Cancer is often a consequence of changes in the expression of a number of genes. These include, dominant-acting oncogenes, tumor suppressor genes, genes affecting cell cycle and genes affecting genomic stability. In the case of tumor suppressor genes, the ability to identify and isolate these elements have proven difficult often involving extensive gene mapping and technically complex and many times unsuccessful molecular approaches. Prior to the art described in this invention, no simple and efficient way of identifying and cloning tumor suppressor genes has been available. The currently described approach is simple and effective in directly identifying potentially novel human tumor suppressor genes and directly cloning these genes. The approach, termed inducible suppression cDNA cloning, is useful in identifying both oncogene specific suppressor genes and global oncogene-independent tumor suppressor genes.
Current knowledge of tumor suppressor genes indicate that they often function as negative regulators of cell growth. Inherent in this operational definition of a tumor suppressor gene is the obvious implication that expression of a tumor suppressor gene in a target cell may evoke a loss of proliferative ability. This possibility has been demonstrated directly by reintroducing cloned tumor suppressor genes through DNA-transfection into tumor cells, i.e., growth and oncogenicity are suppressed. The growth inhibitory effect of tumor suppressor genes has prevented the previous development of functional assays permitting isolation of cells expressing novel tumor suppressor genes (anti-oncogenes).